Craig Coopersmith

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

Are you experienced? Your immune system undoubtedly is. Because of vaccinations and infections, we accumulate memory T cells, which embody the ability of the immune system to respond quickly and effectively to bacteria or viruses it has seen before.

Mandy Ford has teamed up with Craig Coopersmith to investigate sepsis, a relatively new field for her, and the collaboration has blossomed in several directions

“This is an issue we’ve been aware of in transplant immunology for a long time,” says Mandy Ford, scientific director of Emory Transplant Center. “Real life humans have more memory T cells than the mice that we usually study.”

In late-stage sepsis patients, dormant viruses that the immune system usually keeps under control, such as Epstein-Barr virus and cytomegalovirus, emerge from hiding. The situation looks a lot like that in kidney transplant patients, who are taking drugs to prevent immune rejection of their new organ, Ford says.